Patent EP-0818744-A2 (EP)
Inventor: YOUNG STEPHEN CLINTON
IPC: G16B15/30
Filed: 1997-06-24
Abstract: The invention relates to a process for drug candidate
identification, said process comprising the steps of:
   (1) obtaining a computerised representation of the
three-dimensional structure of a binding site on the
surface of a biological macromolecule;   (2) generating a computerised model of the functional
structure of said binding site which may be used to
identify favourable and unfavourable interactions
between the binding site and a drug candidate molecule;   (3) identifying a molecular fragment (or "template" T)
capable of placement within said binding site and
capable of carrying at least one (preferably a plurality
(ie. at least two) and especially preferably at least 3)
substituent group, said molecular fragment either being
capable of being synthesized from reagent compounds
accessible in substituted form whereby to import said
substituent groups on synthesis of said molecular
fragment or being present in an accessible reagent
compound capable of substitution with said substituent
groups by reaction with further accessible reagent
compounds;   (4) generating a set of lists of accessible reagent
compounds (eg. a 1 -A, a 2 -A, a 3 -A, etc, b 1 -B, b 2 -B, b 3 -B,
etc, c 1 -C, c 2 -C, c 3 -C, etc), the lists being such that a
combination of compounds taken from each list (eg. a 1 -A,
b 3 -B and c 11 -C) may be reacted to produce a candidate
compound comprising said molecular fragment carrying a
plurality of substituent groups (eg. a 1 b 3  c 11 T) thereby 
generating a first virtual library of candidate
compounds being the theoretical set of compounds
producible by reaction of the members of said lists (ie.
a 1 b 1 c 1 T, a 1 b 1 c 2 T, a 1 b 2 c 1  T etc), each member of each list
comprising a component (eg. A,B,C, etc.) common to the
other members of that list and a component (eg. a 1 , b 1 ,
c 1 , etc) unique within that list;   (5) for each said list limiting the number of members
thereof using a first set of exclusion rules thereby to
generate a restricted second virtual library of
candidate compounds, the operation of said first set of
rules involving for each member of each list
computerised comparison for favourable or unfavourable
interactions between said computerised model and a
structure comprising said molecular fragment and a
substituent deriving from the unique component within
said list of that member, the molecular fragment and the
computerized model being held in fixed spatial
relationship to each other for said comparison;   (6) evaluating and ranking by computer the members of
said second virtual library for favourable and
unfavourable interactions with said computerised model
and thereby generating a restricted third virtual
library of candidate compounds ranked as having
favourable interactions;   (7) optionally, selecting from said third virtual
library at least one further molecular fragment and
repeating steps (4), (5) and (6) to generate an
alternative third virtual library;   (8) screening said third virtual library using a second
set of exclusion rules thereby to generate a restricted
fourth virtual library of candidate compounds comprising
compounds which are candidates for synthesis and 
experimental evaluation for drug efficacy;   (9) synthesizing some or all candidate compounds of
said fourth virtual library to produce a candidate
compound library;   (10) experimentally evaluating the compounds of said
candidate compound library for drug efficacy;   (11) analysing the experimental efficacy data generated
in step (10) for structure-activity relationship
information;   (12) using the information derived in step (11)
selecting a revised set of lists of accessible reagent
compounds, said lists being expanded to include selected
reagents not present in the restricted lists generated
in step (5) and optionally restricted to exclude
selected reagents present in the restricted lists
generated in step (5);   (13) repeating steps (6) and (7) to identify further
compounds which are candidates for synthesis and
experimental evaluation for drug efficacy;   (14) synthesising and experimentally evaluating said
further compounds for drug efficacy;   (15) if required repeating steps (11) to (14) one or
more times;   (16) identifying as a lead candidate a compound
synthesized and experimentally evaluated as above.    
     The process of the invention is characterised by the
rapid generation of a relatively small set of readily
synthesisable candidate compounds with a high success 
rate in terms of drug efficacy and hence a high
predictive value for directing subsequent iterations.